Abstract
Metastatic recurrence is still a major challenge in breast cancer treatment, but the underlying mechanisms remain unclear. Here, we report that a small adaptor protein, SH3BGRL, is upregulated in the majority of breast cancer patients, especially elevated in those with metastatic relapse, indicating it as a marker for the poor prognosis of breast cancer. Physiologically, SH3BGRL can multifunctionally promote breast cancer cell tumorigenicity, migration, invasiveness, and efficient lung colonization in nude mice. Mechanistically, SH3BGRL downregulates the acting-binding protein profilin 1 (PFN1) by accelerating the translation of the PFN1 E3 ligase, STUB1 via SH3BGRL interaction with ribosomal proteins, or/and enhancing the interaction of PFN1 with STUB1 to accelerate PFN1 degradation. Loss of PFN1 consequently contributes to downstream multiple activations of AKT, NF-kB, and WNT signaling pathways. In contrast, the forced expression of compensatory PFN1 in SH3BGRL-high cells efficiently neutralizes SH3BGRL-induced metastasis and tumorigenesis with PTEN upregulation and PI3K-AKT signaling inactivation. Clinical analysis validates that SH3BGRL expression is negatively correlated with PFN1 and PTEN levels, but positively to the activations of AKT, NF-kB, and WNT signaling pathways in breast patient tissues. Our results thus suggest that SH3BGRL is a valuable prognostic factor and a potential therapeutic target for preventing breast cancer progression and metastasis.
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20 December 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41388-021-02129-1
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Funding
This work was supported by National Science Foundation of China (No. 81672704), the Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population (2018B030322003KF02), and Natural Science Foundation of Guangdong Province (No. 2021A1515010999) to WH.
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S Zhang, S Yang, and H Wang conceived the research and designed the experiments, S Zhang performed the most experiments and data analyses; X Guo collect samples and performed IHC staining with analysis, X Liu performed colony formation assay, XZ Zhong performed Immunoblots of genes in breast cancer tissues; S Zhang, H Wang and S Yang wrote the draft. All authors approved the final manuscript submission.
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Drs. Haihe Wang and Shulan Yang, researchers on the study team, are co-inventors on Patent 201710512823.6 (Sun Yat-sen University) which deals with the application of SH3BGRL as a diagnostic and therapy target. No other authors have competing interests.
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Zhang, S., Guo, X., Liu, X. et al. Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation. Oncogene 40, 5677–5690 (2021). https://doi.org/10.1038/s41388-021-01970-8
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DOI: https://doi.org/10.1038/s41388-021-01970-8